The goal of this R21 proposal is to provide the foundation for future research to examine the utility of the neuropeptide oxytocin (OT) as a new treatment for alcohol use disorders (AUD). Interest in OT as an alcohol treatment stems from its role in adaptive processes including reward, associative learning, memory, and stress responses. Support for its use is based on studies in animal models of addiction showing that OT reduced alcohol reinforcement, attenuated drug tolerance, and decreased withdrawal symptoms. OT exerts its effects via interactions with the hypothalamic-pituitary-adrenal (HPA) axis, as well as dopamine mesolimbic reward and corticotrophin-releasing factor (CRF) stress systems. OT effects on stress systems are of high interest given the strong link between stress, alcohol drinking and relapse, and known dysregulation of HPA-axis activity in heavy drinkers. Both preclinical and clinical evidence provide evidence that OT may help to normalize blunted stress responses, and attenuate alcohol withdrawal associated hypercortisolism, negative mood and withdrawal symptoms. Using gold-standard laboratory procedures in heavy drinkers, we will examine the effects of intranasal OT administration on cortisol stress responses and different measures predictive of alcohol use and misuse under double-blind placebo controlled conditions. Aim 1 will examine the effects of oxytocin on alcohol withdrawal, including symptom severity, alcohol craving, cortisol and negative mood. Aim 2 will examine the effects of oxytocin on response to social stress. Aim 3 will examine the effects of oxytocin on motivation to drink. Aim 4 will examine the effects of oxytocin on alcohol sensitivity. These preliminary data will provide critical information on the potential of OT as a treatment for alcohol drinking problems and will provide the basis for determination of sample sizes for future comprehensive research and clinical trials.